Photochemical Release of Amines by C,N-Bond Cleavage

Abstract

A method for the photorelease of primary and secondary amines using coumarin as chromophore was developed. This mild C,N-bond cleavage reactions liberates the amine not only in solution but also on solid support

photocleavage - coumarin - amine - solid support

References

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1d

Kessler, M.; Glatthar, R.; Giese, B.; Bochet, C. G. Org. Lett. 2003, in press.

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2b James IW. Tetrahedron  1999,  55:  4855 

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5 For a general review on photochemical cleavage reactions of arylmethyl-heteroatom sigma bonds, see: Fleming SA. Pincock JA. In Organic Molecular Photochemistry   Vol. 3:  Ramamurthy V. Schanze KS. Marcel Dekker; New York: 1999.  p.211 

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7

The aminomethyl coumarins 1a-d were synthesized from the commercially available 4-bromomethyl-7-methoxy-coumarin in a substitution reaction with the corresponding amines in the presence of Hünig’s base. The yields are nearly quantitative. Aminomethyl coumarin 1a was irradiated at
20 °C for 30-90 min in methanol with a 500 W Hg high-pressure lamp and a 360 nm cutoff filter. The yields of the cleaved off amine 2a and the coumarin derivatives 5 and 6 [3] were determined by RP-HPLC. The influence of H-donors was checked by adding 50 equiv 1,4-cyclohexadiene or
n-decanethiol before irradiation.

8

Experimental conditions for the photocleavage of 1a:
A solution of aminomethyl coumarin 1a (47.0 mg, 0.145 mmol), n-decanethiol (3.10 mL, 14.5 mmol) and 1 M HCl (233 L, 0.218 mmol) in methanol (120 mL) was purged for 20 min with argon and irradiated with a 150 W Hg middle-pressure lamp with a pyrex coating for 30 min under continuous cooling with water (15 °C). For the separation of the amine 2a, 3 M aqueous NH₄Cl solution (50 mL) was added, methanol was evaporated and the residue was washed with CH₂Cl₂ (3 × 50 mL). The aqueous solution was basified, extracted with diethyl ether (5 × 50 mL), dried over MgSO₄ and concentrated under reduced pressure, yielding 16.6 mg (0.123 mmol, 85%) of amine 2a.

9

Synthesis of 12: Umbeliferon 7 was alkylated under basic conditions with tert-butyl protected 5-bromovaleric acid yielding 7-alkoxy-substituted coumarin 8. The oxidation of 8 with selenium dioxide [17] gave aldehyde 9 after deprotection of the tert-butyl ester with trifluoroacetic acid. [18] Coupling of 9 with commercially available amino support (TentaGel S-NH₂) was performed with diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBT) in CH₂Cl₂/DMF, yielding the aldehyde linker 10. The anchoring proceeded with complete conversion as determined by the Kaiser test. [19] The amine coupling, forming 12, was conducted on solid phase after reduction of 10 with tetrabutylammonium boro-hydride, [20] subsequent Appel bromination (CBr₄, PPh₃), [21] and nucleophilic substitution of the bromide 11 with the amine 2a in the presence of Hünig’s base. An alternative way of coupling the amine to the solid support is the reductive amination of aldehyde 10 with amine 2a in the presence of NaBH(OAc)₃ and acetic acid. [22] All reaction steps were checked by gel-phase ¹³C NMR. [23] Picric acid monitoring showed that resin 12 was obtained with 0.112 mmol/g loading of amine 2a. [24]

10

C,N-Cleavage at the solid support (12→2a): Photolyses in quartz glass cells (500 W Hg high-pressure lamp fitted with a 360 nm cutoff filter) were conducted with about 20 mg of resin 12 suspended in 2.5 mL of methanol in the presence of n-decanethiol (100 equiv). In order to stabilize the cleaved off amine 2a 1 M HCl (1.5 equiv) was added. The cells were maintained at 20 °C and irradiated for 3 hours with gentle mixing of the beads by means of a magnetic stirrer. After photolysis, the supernatant was analyzed by reversed-phase HPLC using an internal standard. The amount of cleaved amine 2a was 80%, based on the loading of resin 12.

11a Furuta T. Torigai H. Sugimoto M. Iwamura M. J. Org. Chem.  1995,  60:  3953 

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12 A similar experiment had been carried out with a dimethylaminomethyl coumarin derivative by: De Silva AP. Gunaratne HQN. Lynch PL. Patty AJ. Spence GL. J. Chem. Soc., Perkin Trans. 2  1993,  1611 

13

The electron transfer step (1→13) generating a ketyl radical anion functionality is important for the C,N-bond cleavage reaction. Thus, even quaternary ammonium salts like 3 cannot be cleaved photolytically if the electron donating borate is exchanged by a non-reducing anion. [3] In a similar way, the addition of large amounts of acids to 1 retarded or even inhibited the photocleavage.

14

In the abstraction step by the mesomeric stabilized radical 15 an H-atom might not only be donated to the methyl radical center but also to C-3 or the carbonyl oxygen of the coumarin system. Under our conditions we have observed only 5.

15a Kaholek M. Hrdlovic P. J. Photochem. Photobiol. A: Chem.  1999,  127:  45 

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16

The structures of compounds 17 and 18 were determined by NMR. Compound 17 was not stable under the photolytic conditions and gave isomer 18 and methylcoumarin 5 under further irradiation. This reaction is presumably initiated by the cleavage of the C,S-bond (17→15). It is very likely that compound 18 is formed after recombination at C-3 of the coumarin radical and the thiyl radical with subsequent isomerization.

17 Ito K. Nakajima KJ. Heterocyclic Chem.  1988,  25:  511 

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